Lysine deacetylation inhibition reverses TDP-43 mislocalization and in combination with arimoclomol ameliorates neuromuscular pathology

Cytoplasmic inclusions containing TAR DNA-binding protein 43 kDa (TDP-43) are recognized as a major pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Cyclophilin A (PPIA) interacts with TDP-43 and influences its aggregation and function. This interaction is facilitated by PPIA Lys-acetylation. We investigated the effect of lysine deacetylation inhibition to uncover the underlying mechanisms of TDP-43 proteinopathy in relation to PPIA acetylation, and to identify new therapeutic avenues. Through a screening of histone deacetylase (HDAC) inhibitors in a cellular model of TDP-43 proteinopathy, we identified vorinostat/SAHA, capable of increasing PPIA acetylation, as the most effective in reversing TDP-43 mislocalization. We confirmed its effect in PBMCs from ALS patients and explored its impact on proteinopathy and PPIA acetylation in the Thy1-hTDP-43 mouse model. Thy1-hTDP-43 mice treated with SAHA showed a delayed onset of TDP-43 pathology, associated with PPIA nucleus-cytoplasm redistribution, lower neurodegeneration and neuroinflammation, and improved neuromuscular function markers. However, the effect was only temporary. When combined with the heat shock protein (HSP) co-inducer arimoclomol, a mitigation of the neurodegeneration was sustained. A synergistic effect was observed in periphery, greatly enhancing tubulin acetylation and reducing pTDP-43 accumulation in the sciatic nerve and acetylcholine receptor (AChR) {gamma}-subunit expression in gastrocnemius muscle. This study suggests that HDAC inhibition, by increasing acetylated PPIA, could be beneficial in restoring TDP-43 localization and function. The combination of lysine deacetylation inhibition and HSP induction shows a synergistic effect in vivo and has potential as a therapeutic approach for patients.